1
Introduction

The Agent Orange Act of 1991 (Public Law [PL] 102-4, enacted February 6, 1991, and codified as 38 USC Sec. 1116) directed the Secretary of Veterans Affairs to ask the National Academy of Sciences (NAS) to conduct an independent comprehensive review and evaluation of scientific and medical information regarding the health effects of exposure to herbicides used during military operations in Vietnam. The herbicides picloram and cacodylic acid were to be addressed, as were chemicals in various formulations containing the herbicides 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T). The most well known of the formulations, Agent Orange, was a 50:50 mixture of the herbicides 2,4-D and 2,4,5-T, which contained the contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD); thus, it should be noted that TCDD and Agent Orange are not synonymous. NAS also was asked to recommend, as appropriate, additional studies to resolve continuing scientific uncertainties and to comment on particular programs mandated in the law. In addition, the legislation called for biennial reviews of newly available information for a period of 10 years; the period was extended to 2014 by the Veterans Education and Benefits Expansion Act of 2001 (PL 107-103).

In response to the request from the Department of Veterans Affairs (VA), the Institute of Medicine (IOM) of NAS convened the Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides. The results of the original committee’s work were published in 1994 as Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam, hereafter referred to as VAO (IOM, 1994). Successor committees formed to fulfill the requirement for updated reviews produced Veterans and Agent Orange: Update 1996 (IOM, 1996), Up-

Citation Manager

Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter.
Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.

OCR for page 17
1
Introduction
The Agent Orange Act of 1991 (Public Law [PL] 102-4, enacted February
6, 1991, and codiﬁed as 38 USC Sec. 1116) directed the Secretary of Veterans
Affairs to ask the National Academy of Sciences (NAS) to conduct an indepen-
dent comprehensive review and evaluation of scientiﬁc and medical informa-
tion regarding the health effects of exposure to herbicides used during military
operations in Vietnam. The herbicides picloram and cacodylic acid were to be
addressed, as were chemicals in various formulations containing the herbicides
2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid
(2,4,5-T). The most well known of the formulations, Agent Orange, was a 50:50
mixture of the herbicides 2,4-D and 2,4,5-T, which contained the contaminant
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD); thus, it should be noted that TCDD
and Agent Orange are not synonymous. NAS also was asked to recommend, as
appropriate, additional studies to resolve continuing scientiﬁc uncertainties and
to comment on particular programs mandated in the law. In addition, the legisla-
tion called for biennial reviews of newly available information for a period of 10
years; the period was extended to 2014 by the Veterans Education and Beneﬁts
Expansion Act of 2001 (PL 107-103).
In response to the request from the Department of Veterans Affairs (VA),
the Institute of Medicine (IOM) of NAS convened the Committee to Review the
Health Effects in Vietnam Veterans of Exposure to Herbicides. The results of the
original committee’s work were published in 1994 as Veterans and Agent Or-
ange: Health Effects of Herbicides Used in Vietnam, hereafter referred to as VAO
(IOM, 1994). Successor committees formed to fulﬁll the requirement for updated
reviews produced Veterans and Agent Orange: Update 1996 (IOM, 1996), Up-
17

OCR for page 17
18 VETERANS AND AGENT ORANGE: UPDATE 2006
date 1998 (IOM, 1999), Update 2000 (IOM, 2001), Update 2002 (IOM, 2003),
and Update 2004 (IOM, 2005). In 1999, VA asked IOM to convene a committee
to conduct an interim review of type 2 diabetes; that effort resulted in the report
Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes,
hereafter referred to as Type 2 Diabetes (IOM, 2000). In 2001, VA asked IOM
to convene a committee to conduct an interim review of childhood acute my-
elogenous leukemia (AML) associated with parental exposure; its review of the
literature, including literature available since the review for Update 2000, was
published in Veterans and Agent Orange: Herbicide/Dioxin Exposure and Acute
Myelogenous Leukemia in the Children of Vietnam Veterans, hereafter referred to
as Acute Myelogenous Leukemia (IOM, 2002). Also in 2001, Congress (PL 107-
103) directed the Secretary of Veterans Affairs to ask NAS to review “available
scientiﬁc literature on the effects of exposure to an herbicide agent containing
dioxin on the development of respiratory cancers in humans” and to address
“whether it is possible to identify a period of time after exposure to herbicides
after which a presumption of service-connection” of the disease would not be
warranted; the result of that effort was Veterans and Agent Orange: Length of
Presumptive Period for Association Between Exposure and Respiratory Cancer,
hereafter referred to as Respiratory Cancer (IOM, 2004).
In conducting their work, the committees responsible for those reports oper-
ated independently of VA and other government agencies. They were not asked to
and did not make judgments regarding speciﬁc cases in which individual Vietnam
veterans have claimed injury from herbicide exposure. The reports were intended
to provide scientiﬁc information for the Secretary of Veterans Affairs to consider
as VA exercises its responsibilities to Vietnam veterans.
CHARGE TO THE COMMITTEE
In accordance with PL 102-4, the committee was asked to “determine (to
the extent that available scientiﬁc data permit meaningful determinations)” the
following regarding associations between speciﬁc health outcomes and exposure
to TCDD and other chemical compounds in herbicides:
A) whether a statistical association with herbicide exposure exists, taking into
account the strength of the scientiﬁc evidence and the appropriateness of the
statistical and epidemiological methods used to detect the association;
B) the increased risk of the disease among those exposed to herbicides during
service in the Republic of Vietnam during the Vietnam era; and
C) whether there exists a plausible biological mechanism or other evidence of a
causal relationship between herbicide exposure and the disease.
The committee notes that both its congressional mandate and the statement
of task are phrased with the target of evaluation being “association,” not “causal-

OCR for page 17
19
INTRODUCTION
ity,” between exposure and health outcomes. As used technically, the criteria for
causation are somewhat more stringent than those for association. The standard
of association was not the choice of VAO committees, but the consequence of
congressional and judicial history. IOM has recently convened a separate com-
mittee to evaluate VA’s methods of determining whether medical conditions are
service-related; that committee will address this and other issues.
In delivering the above charge to the current committee, the VA project
ofﬁcer made two additional speciﬁc requests. First, he asked the committee to
examine the evidence related to whether the occurrence of AML, tonsil cancer,
AL amyloidosis, and lupus may be associated with exposure to the components
of herbicides used by the military in Vietnam. Second, he made the more general
request that the appropriate category of association be explicitly indicated for all
forms of cancer, leaving no gaps in the exhaustive range of codes for malignant
neoplasms (ICD-9 140–208, according to the International Classiﬁcation of
Diseases, Ninth Edition).
Details of the committee’s approach to its charge and the methods it used
in reaching conclusions are provided in Chapter 2 and elaborated on in the
health-outcome chapters, particularly Chapter 6, on evidence concerning speciﬁc
cancers.
CONCLUSIONS OF PREVIOUS VETERANS
AND AGENT ORANGE REPORTS
Health Outcomes
VAO, Update 1996, Update 1998, Update 2000, Update 2002, Update 2004,
Type 2 Diabetes, Acute Myelogenous Leukemia, and Respiratory Cancer provide
detailed reviews of the scientiﬁc studies evaluated by the committees and their
implications for cancer, reproductive and developmental effects, neurobehavioral
disorders, and other health effects.
The original committee addressed the statutory mandate to determine whether
there is a statistical association between a given health effect and herbicide expo-
sure by assigning each of the health outcomes under study to one of four catego-
ries on the basis of the epidemiologic evidence reviewed. Those categories were
adapted from the ones used by the International Agency for Research on Cancer
(IARC) in evaluating evidence of the carcinogenicity of various substances
(IARC, 1977). Successor committees adopted the same categories.
The establishment of categories regarding the evidence for “statistical asso-
ciation,” rather than “causality,” has been controversial. It should be noted, how-
ever, that this principle was established in legal proceedings that predate passage
of the legislation mandating the VAO series of reviews. Nehmer vs United States
Veterans Administration (712 F. Supp. 1404, 1989) found that:

OCR for page 17
20 VETERANS AND AGENT ORANGE: UPDATE 2006
The legislative history, and prior VA and congressional practice, support our
ﬁnding that Congress intended that the Administrator predicate service con-
nection upon a ﬁnding of a signiﬁcant statistical association between dioxin
exposure and various diseases. We hold that the VA erred by requiring proof of
a causal relationship.
The categories, the criteria for assigning a particular health outcome to a cat-
egory, and the health outcomes that have been assigned to the categories in past
updates are discussed below. Table 1-1 summarizes the conclusions of Update
2004 (IOM, 2005) regarding associations between health outcomes and exposure
to the herbicides used in Vietnam or to any of their components or contaminants.
This integration of the literature to 2004 served as the starting point for the cur-
rent committee’s deliberations. It should be noted that the categories of associa-
tion concern the occurrence of health outcomes in human populations in relation
to chemical exposures; they do not address the likelihood that any individual’s
health problem is associated with or caused by the chemicals in question.
Health Outcomes with Sufﬁcient Evidence of an Association
In this category, a positive association between herbicides and the outcome
must be observed in studies in which chance, bias, and confounding can be ruled
out with reasonable conﬁdence. The committee regarded evidence from several
small studies that have satisfactorily addressed bias and confounding and that
show an association that is consistent in magnitude and direction as sufﬁcient
evidence of an association.
The original committee found sufﬁcient evidence of an association between
exposure to herbicides and three cancers—soft-tissue sarcoma, non-Hodgkin’s
lymphoma, and Hodgkin’s disease—and two other health outcomes, chloracne
and porphyria cutanea tarda (PCT) (IOM, 1994). After reviewing all the literature
available in 1995, the committee responsible for Update 1996 concluded that the
statistical evidence still supported that classiﬁcation for the three cancers and
chloracne but that the evidence of an association with PCT warranted its being
placed in the category of limited or suggestive evidence of an association with
exposure; Chapter 11 of Update 1996 details the decision. No changes were made
in this category in Update 1998 or Update 2000.
As the committee responsible for Update 2002 began its work, VA requested
that it evaluate whether chronic lymphocytic leukemia (CLL) should be consid-
ered separately from other leukemias. The committee concluded that CLL could
be considered separately and, on the basis of the given epidemiologic literature
and the etiology of the disease, placed CLL in the “sufﬁcient” category.

OCR for page 17
22 VETERANS AND AGENT ORANGE: UPDATE 2006
TABLE 1-1 Continued
AL amyloidosis
Endometriosis
Effects on thyroid homeostasis
Limited or Suggestive Evidence of No Association
Gastrointestinal tumors (stomach, pancreas, colon, and rectum)
Brain tumors
Spontaneous abortion and paternal exposure to TCDDb
a Herbicides indicates the following chemicals of interest: 2,4-dichlorophenoxyacetic acid (2,4-D),
2,4,5-trichlorophenoxyacetic acid (2,4,5-T) and its contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin
(TCDD, or dioxin), cacodylic acid, and picloram. The evidence regarding association was drawn from
occupational, environmental, and veteran studies in which people were exposed to the herbicides used
in Vietnam, to their components, or to their contaminants.
b New ﬁnding from Update 2002, which had not been listed in previous summary tables.
Health Outcomes with Limited or Suggestive Evidence of an Association
In this category, the evidence must suggest an association between exposure
to herbicides and the outcome considered, but the evidence can be limited by
the inability to rule out chance, bias, or confounding conﬁdently. The wording
“For example, at least one high-quality study shows a positive association, but
the results of other studies are inconsistent” has appeared in prior VAO reports.
The present committee interpreted that statement as an example of one particular
situation. The coherence of the full body of epidemiologic information, in light of
biologic plausibility, is considered when the committee reaches a judgment about
association for a given endpoint. Because the VAO series has four herbicides and
TCDD as agents of concern whose proﬁles of toxicity are not expected to be
uniform, apparent inconsistencies can be expected among study populations that
have experienced different exposures. Even for a single exposure, a spectrum
of results would be expected, depending on the power of the studies and other
design factors. If the committee encountered a high-quality study showing an
association for a given health outcome in a body of evidence that also contained
a high-quality study showing strong negative ﬁndings on exposure to the same
agent, it would not automatically adopt a classiﬁcation of limited or suggestive
evidence of an association.
The committee responsible for VAO found limited or suggestive evidence
of an association between exposure to herbicides and three categories of cancer:
respiratory cancer (after individual evaluations of laryngeal cancer and of cancers
of the trachea, lung, or bronchus), prostate cancer, and multiple myeloma. The
Update 1996 committee added three health outcomes to the list: PCT, acute and
subacute transient peripheral neuropathy (hereafter called early-onset transient

OCR for page 17
23
INTRODUCTION
peripheral neuropathy), and spina biﬁda in children of veterans. Transient periph-
eral neuropathies had not been addressed in VAO, because they are not amenable
to epidemiologic study. In response to a VA request, however, the Update 1996
committee reviewed those neuropathies and based its determination on case his-
tories (Update 1996, Chapter 10). A 1995 analysis of birth defects among the off-
spring of veterans who served in Operation Ranch Hand, combined with earlier
studies of neural-tube defects in the children of Vietnam veterans (published by
the Centers for Disease Control and Prevention), led the Update 1996 committee
to distinguish spina biﬁda from other reproductive outcomes and to classify it
in the “limited or suggestive evidence” category (Update 1996, Chapter 9). No
changes were made in this category in Update 1998.
After the publication of Update 1998, on the basis of its evaluation of newly
available scientiﬁc evidence and the cumulative ﬁndings of research reviewed in
previous VAO reports, the committee responsible for Type 2 Diabetes concluded
that there was limited or suggestive evidence of an association between exposure
to the herbicides used in Vietnam or the contaminant TCDD and type 2 diabetes
(mellitus). The evidence reviewed in Update 2000 supported that ﬁnding.
The committee responsible for Update 2000 reviewed the material in earlier
reports and the newly published literature and determined that there was limited
or suggestive evidence of an association between exposure to herbicides used in
Vietnam or the contaminant TCDD and AML in the children of Vietnam veterans.
After release of that report, researchers on one of the studies reviewed in Up-
date 2000 discovered an error in the published data. The committee for Update
2000 was reconvened to re-evaluate the previously reviewed and new literature
regarding that illness. It produced the Acute Myelogenous Leukemia report, which
reclassiﬁed AML in children from “limited or suggestive evidence of an associa-
tion” to “inadequate evidence to determine an association.”
Health Outcomes with Inadequate or Insufﬁcient
Evidence to Determine an Association
By default, any health outcome is in this category before enough reliable
scientiﬁc data accumulate to promote it to the category of sufﬁcient evidence
or limited or suggestive evidence of an association or to the category of limited
or suggestive evidence of no association. In this category, available studies may
have inconsistent ﬁndings or be of insufﬁcient quality or statistical power to sup-
port a conclusion regarding the presence of an association. Such studies might
have failed to control for confounding or might have had inadequate assessment
of exposure.
The cancers and other health effects so categorized in Update 2004 are
listed in Table 1-1, but several health effects have been moved into or out of this
category since the original VAO committee reviewed the evidence then available.
Skin cancer was moved into this category in Update 1996 when inclusion of

OCR for page 17
24 VETERANS AND AGENT ORANGE: UPDATE 2006
new evidence no longer supported its classiﬁcation as a condition with limited
or suggestive evidence of no association. Similarly, the Update 1998 committee
moved urinary bladder cancer from the category of limited or suggestive evidence
of no association to this category; although there was no evidence that exposure
to herbicides or TCDD is related to urinary bladder cancer, newly available evi-
dence weakened the evidence of no association. The committee for Update 2000
had partitioned AML in the offspring of Vietnam veterans from other childhood
cancers and put it into the category of suggestive evidence; but a separate review,
as reported in Acute Myelogenous Leukemia (IOM, 2002), found errors in the
published information and returned it to the category of inadequate or insufﬁcient
evidence with other childhood cancers. In Update 2002, CLL was moved from
this category to join Hodgkin’s and non-Hodgkin’s lymphomas in the category
of sufﬁcient evidence of an association.
Health Outcomes with Limited or Suggestive Evidence of No Association
The original VAO committee deﬁned this category for health outcomes for
which there were several adequate studies covering the “full range of human
exposure” that were consistent in showing no association between exposure to
herbicides at any level and the outcome and that had relatively narrow conﬁdence
intervals. A conclusion of “no association” is inevitably limited to the condi-
tions, exposures, and observation period covered by the available studies. The
possibility of a small increase in risk at the levels of exposure studied can never
be excluded. However, a change in classiﬁcation from inadequate or insufﬁcient
evidence to limited or suggestive evidence of no association would require new
studies that correct for the methodologic problems of previous studies and that
have samples large enough to limit the possible study results attributable to
chance.
The original VAO committee found a sufﬁcient number and variety of well-
designed studies to conclude that there was limited or suggestive evidence of
no association between the exposures of interest and a small group of cancers:
gastrointestinal tumors (colon, rectum, stomach, and pancreas), skin cancers,
brain tumors, and urinary bladder cancer. The Update 1996 committee removed
skin cancers and the Update 1998 committee removed urinary bladder cancer
from this category because the evidence no longer supported a conclusion of
no association. The Update 2002 committee concluded that there was adequate
evidence to determine that spontaneous abortion is not associated with paternal
exposure speciﬁcally to TCDD; the evidence for this endpoint was deemed inad-
equate for drawing a conclusion about association for maternal exposure overall
or for paternal exposure to any other of the chemicals of interest. No changes in
this category were made in Update 2000, or Update 2004. As will be discussed
in greater detail in this volume, the current committee was concerned that the
overall paucity of information on picloram and cacodylic acid make this asser-

OCR for page 17
25
INTRODUCTION
tion questionable for the endpoints (brain cancer and several digestive cancers)
remaining in this category.
Determining Increased Risk in Vietnam Veterans
The second part of the committee’s charge is to determine, to the extent
permitted by available scientiﬁc data, the increased risk of disease among people
exposed to herbicides during service in Vietnam. Previous reports point out that
most of the many health studies of Vietnam veterans are hampered by relatively
poor measures of exposure to herbicides or TCDD and by other methodologic
problems. Most of the evidence on which the ﬁndings regarding associations are
based, therefore, comes from studies of people exposed to TCDD or herbicides
in occupational and environmental settings rather than from studies of Vietnam
veterans. The committees that produced VAO and the updates found that the body
of evidence was sufﬁcient for reaching conclusions about statistical associations
between herbicide exposures and health outcomes but that the lack of adequate
data on Vietnam veterans themselves complicated consideration of the second
part of the charge.
The evidence of herbicide exposure among various groups studied suggests
that most Vietnam veterans (except those with documented high exposures, such
as participants in Operation Ranch Hand or the Army Chemical Corps) had lower
exposures to herbicides and TCDD than did the subjects of many occupational
and environmental studies. Individual veterans who had very high exposures to
herbicides, however, could have risks approaching those described in the occu-
pational and environmental studies.
Estimating the magnitude of risk of each particular health outcome among
herbicide-exposed Vietnam veterans requires quantitative information about the
dose–time–response relationship for the health outcome in humans, information
on the extent of herbicide exposure among Vietnam veterans, and estimates of
individual exposure. Previous committees have concluded that in general it is
impossible to quantify the degree of risk likely to be experienced by veterans
because of their exposure to herbicides in Vietnam. Overall statements to that
effect were made in VAO (IOM, 1994) and in every update, but uniformity in
the set explanations about the unavailability of the necessary information for
performance of quantitative risk assessment for Vietnam veterans in the conclud-
ing section for each health outcome or in chapter summaries became somewhat
idiosyncratic over the course of the updates. In an effort to streamline the presen-
tation for the individual health outcomes, the point will no longer be reiterated
in each instance. The present committee has chosen to eliminate the repetitive
restatements in favor of the following general conclusion: At least for the present,
it is not possible to derive quantitative estimates of the increase in risk of various
adverse health effects that Vietnam veterans may have experienced in association
with exposure to the herbicides sprayed in Vietnam.

OCR for page 17
26 VETERANS AND AGENT ORANGE: UPDATE 2006
After decades of research, the challenge of estimating the magnitude of po-
tential risk posed by exposure to the compounds of interest remains intractable.
The requisite information is still absent despite concerted efforts to reconstruct
likely exposure by modeling based on records of troop movements and spray-
ing missions (Stellman et al., 2003a,b; Stellman and Stellman, 2003, 2004), to
measure serum TCDD in individual veterans (Kang et al., 2006; Michalek et al.,
1995), and to model the pharmacokinetics of TCDD clearance (Aylward et al.,
2005a,b; Cheng et al., 2006b; Emond et al., 2004, 2005, 2006). Uncertainty re-
mains about the speciﬁc agent that may be responsible for a particular health ef-
fect. Even if one accepts an individual veteran’s serum TCDD level as the optimal
surrogate for his overall exposure to Agent Orange and the other herbicide mix-
tures sprayed in Vietnam, not only is the measurement nontrivial but the hurdle
of accounting for biologic clearance and extrapolating to the proper timeframe
remains. The committee therefore believes that it cannot accurately estimate the
risk to Vietnam veterans that is attributable to exposure to the compounds associ-
ated with herbicide spraying in Vietnam.
Existence of a Plausible Biologic Mechanism or
Other Evidence of a Causal Relationship
Toxicologic data form the basis of the committee’s response to the third part
of its charge—to determine whether there is a plausible biologic mechanism or
other evidence of a causal relationship between herbicide exposure and a health
effect. That information is summarized in general terms in separate toxicology
chapters in previous reports: Chapter 4 of VAO and Chapter 3 of Update 1996,
Update 1998, Update 2000, Update 2002, and Update 2004. An analogous
chapter in this update summarizes recent toxicologic ﬁndings on the chemicals
of concern, and speciﬁc ﬁndings on each health outcome are also given in the
chapters that review the epidemiologic literature.
In previous updates, this topic has been discussed in the conclusions section
for each health outcome after a statement of the committee’s judgment about the
adequacy of the epidemiologic evidence of an association of that outcome with
exposure to the chemicals of interest. In fact, the degree of biologic plausibility
itself inﬂuences whether the committee perceives positive ﬁndings to be indica-
tive of a pattern or the product of statistical ﬂuctuations. To provide the reader
with a more logical sequence, biologic-plausibility sections have been placed
between the presentation of new epidemiologic evidence and the synthesis of all
the evidence, which in turn leads to the ultimate statement of the committee’s
conclusion.

OCR for page 17
27
INTRODUCTION
ORGANIZATION OF THIS REPORT
The remainder of this report is organized in nine chapters. Chapter 2 brieﬂy
describes the considerations that guided the committee’s review and evaluation
of the scientiﬁc evidence. Chapter 3 updates the toxicology data on the effects of
2,4-D, 2,4,5-T and its contaminant TCDD, cacodylic acid, and picloram; those
data contribute to the biologic plausibility of health effects in human populations.
Chapter 4 provides an overview of populations repeatedly studied in the course
of investigating the toxic potential of the chemicals of interest in this report; it
also gives design information on the epidemiologic studies new in this update that
investigated those populations or that report multiple health outcomes. Chapter 5
addresses exposure-assessment issues and the exposure assessments conducted
in the studies of the major cohorts. The committee’s evaluation of the epidemio-
logic literature and its conclusions regarding associations between the exposures
of interest and cancer, reproductive and developmental effects, neurobehavioral
disorders, and other health effects are discussed in Chapters 6, 7, 8, and 9, respec-
tively. The committee’s research recommendations are presented in Chapter 10.
REFERENCES1
Aylward LL, Brunet RC, Carrier G, Hays SM, Cushing CA, Needham LL, Patterson DG Jr, Gerthoux
PM, Brambilla P, Mocarelli P. 2005a. Concentration-dependent TCDD elimination kinetics in
humans: Toxicokinetic modeling for moderately to highly exposed adults from Seveso, Italy,
and Vienna, Austria, and impact on dose estimates for the NIOSH cohort. Journal of Exposure
Analysis and Environmental Epidemiology 15(1):51−65.
Aylward LL, Brunet RC, Starr TB, Carrier G, Delzell E, Cheng H, Beall C. 2005b. Exposure recon-
struction for the TCDD-exposed NIOSH cohort using a concentration- and age-dependent model
of elimination. Risk Analysis 25(4):945−956.
Cheng H, Aylward L, Beall C, Starr TB, Brunet RC, Carrier G, Delzell E. 2006b. TCDD exposure-
response analysis and risk assessment. Risk Analysis 26(4):1059−1071.
Emond C, Birnbaum LS, DeVito MJ. 2004. Physiologically based pharmacokinetic model for devel-
opmental exposures to TCDD in the rat. Toxicological Sciences 80(1):115−133.
Emond C, Michalek JE, Birnbaum LS, DeVito MJ. 2005. Comparison of the use of physiologically
based pharmacokinetic model and a classical pharmacokinetic model for dioxin exposure as-
sessments. Environmental Health Perspectives 113(12):1666−1668.
Emond C, Birnbaum LS, DeVito MJ. 2006. Use of a physiologically based pharmacokinetic model for
rats to study the inﬂuence of body fat mass and induction of CYP1A2 on the pharmacokinetics
of TCDD. Environmental Health Perspectives 114(9):1394−1400.
IARC (International Agency for Research on Cancer). 1977. Some Fumigants, the Herbicides 2,4-
D and 2,4,5-T, Chlorinated Dibenzodioxins and Miscellaneous Industrial Chemicals. IARC
Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man, Vol. 15. Lyon,
France: World Health Organization, IARC.
1Throughout the report the same alphabetic indicator following year of publication is used con-
sistently for the same article when there were multiple citations by the same ﬁrst author in a given
year. The convention of assigning the alphabetic indicator in order of citation in a given chapter is
not followed.

Bookmark this page

Important Notice

As of 2013, the National Science Education Standards have been replaced by the Next Generation Science Standards (NGSS), available as a print book, free PDF download, and online with our OpenBook platform.